Metformin is an orally administered drug used to lower blood glucose levels in patients with non-insulin dependent diabetes mellitus (NIDDM). In addition to its favorable effects on glucose metabolism, recent studies have shown that metformin lowers blood pressure in NIDDM patients with secondary hypertension. Of the potential anti-hypertensive mechanisms of metformin, a decrease in sympathetic nerve activity and a diminution in vascular reactivity are the most well established. In recent studies, for example, we have shown that acute decreases in blood pressure to metformin are abolished by sympathetic blockade. Others have demonstrated that short-term incubation of vascular smooth muscle in metformin reduces contractile responses to a variety of pressor agents. It remains unclear, however, whether results from these acute experiments can be extrapolated to responses observed during long-term blood pressure reduction with metformin. To address this question, the present research plan will examine whether long-term metformin causes chronic decreases in blood pressure by inhibiting sympathetic neural outflow and by reducing vascular reactivity. Specifically, will be determined whether three weeks of metformin, delivered in the drinking water, reduces plasma catecholamine levels in spontaneously hypertensive rats (SHRs). We will additionally examine whether metformin reduces the magnitude of the fall in blood pressure produced by ganglion blockade, and if metformin is able to affect blood pressure in rats with permanent sympathectomy. Finally, it will be determined whether three weeks of metformin reduces the reactivity of the cardiovascular system to selected pressor agents. Because little is known about how metformin interacts with the cardiovascular system, results from the proposed studies will extend our knowledge about how metformin lowers blood pressure in hypertensive humans with NIDDM and will help to determine which hypertensive patients will most benefit from treatment with this drug.